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NLRP3-mediated inflammation in cardio-oncology: sterile yet harmful

Published:August 06, 2022DOI:https://doi.org/10.1016/j.trsl.2022.08.004

      Abstract

      Despite significant advances and the continuous development of novel, effective therapies to treat a variety of malignancies, cancer therapy-induced cardiotoxicity has been identified as a prominent cause of morbidity and mortality, closely competing with secondary malignancies. This unfortunate limitation has prompted the inception of the field of cardio-oncology with its purpose to provide the necessary knowledge and key information on mechanisms that support the use of the most efficacious cancer therapy with minimal or no interruption while paying close attention to preventing cardiovascular related morbidity and mortality. Several mechanisms that contribute to cancer therapy-induced cardiotoxicity have been proposed and studied. These mainly involve mitochondrial dysfunction and reactive oxygen species-induced oxidative stress, lysosomal damage, impaired autophagy, cell senescence, DNA damage, and sterile inflammation with the formation and activation of the NLRP3 inflammasome. In this review, we focus on describing the principal mechanisms for different classes of cancer therapies that lead to cardiotoxicity involving the NLRP3 inflammasome. We also summarize current evidence of cardio-protection with inflammasome inhibitors in the context of heart disease in general, and further highlight the potential application of this evidence for clinical translation in at risk patients for the purpose of preventing cancer therapy associated cardiovascular morbidity and mortality.

      Abbreviation:

      AF (Atrial fibrillation), AICM (Anthracycline-induced cardiomyopathy), AKT (Protein kinase B), ALR (AIM2-like receptor), AMI (Acute myocardial infarction), ASC (Apoptosis-associated speck-like protein containing a CARD domain), BMDM (Bone marrow-derived macrophages), Ca2+ (Calcium), CaMKIIδ (Ca2+/calmodulin-dependent protein kinase II δ), CAPS (Cryopyrin-associated periodic syndrome), CARD (Carboxy-terminal caspase recruitment domain), CHF (Congestive heart failure), CVB3 (Coxsackievirus B3), DAMPS (Danger-associated molecular patterns), DOX (Doxorubicin), EGFR (Epidermal-grow factor receptor), ER (Endoplasmic reticulum), FDA (Food and Drug Administration), FGFR (Fibroblast grow factor receptor), GDP (Guanosine diphosphate), GSDMD (Gasdermin D), H2S (Hydrogen sulfide), HER2 (Human epidermal growth factor receptor 2), HFpEF (Heart failure with preserved ejection fraction), HFrEF (Heart failure with reduced ejection fraction), ICI (Immune checkpoint inhibitor), IKKβ (Inhibitor for kappa B kinase β), IL-18 (Interleukin-18), IL-1Ra (Recombinant IL-1 receptor antagonist), IL-1RI (Interleukin-1 receptor type I), IL-1β (Interleukin-1β), K+ (Potassium), LDLR (Low-density lipoprotein receptor), LRR (Leucine-rich repeats), LV (Left ventricular), LVEF (Left ventricular ejection fraction), MAPK (Mitogen-activated protein kinase), mtDNA (Mitochondrial DNA), Na2S (Sodium sulfide), NaHS (Sodium hydrosulfide), NEK (NIMA-related kinases proteins), NF-kB (Nuclear factor kappa-light-chain-enhancer of activated B cells), NLR ((NOD)-like receptors), NLRP3 (Nod-like receptor protein 3), NOD (Nucleotide-binding and oligomerization domain), NRTK (Non-receptor tyrosine kinase), NTproBNP (N-terminal-pro hormone B-type natriuretic peptide), PAMPS (Pathogen-associated molecular patterns), PDGFR (Platelet-derived grow factor receptor), PI3K (Phosphoinositide 3 Kinase), PRR (Pattern recognition receptor), PYD (Pyrin domain), RAGE (Receptor for advanced glycation end-products), ROS (Reactive oxygen species), RT (Radiation therapy), RTK (Receptor tyrosine kinases), SGLT2 (Sodium-glucose Cotransporter-2), TK (Tyrosine kinases), TKI (Tyrosine kinase inhibitors), TLR (Toll-like receptors), TXNIP (Thioredoxin-interacting protein), VEGFR (Vascular endothelial growth factor), VO2 (against medical advice)
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